PMX53 protects spinal cord from ischemia-reperfusion injury in rats in the short term

Abstract

Study design: Experimental study. Objectives: To investigate the effect of pre-treatment with PMX53, a C5aR antagonist, on spinal cord ischemia-reperfusion injury (IRI) in rat. Setting: Department of Neurosurgery, Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi Province, China. Methods: IRI was induced in the lumbar spinal cord by applying a mini aneurysm clamp to the abdominal aorta for 60 min in adult Sprague-Dawley rats. PMX53 (1 mg kg − 1 ) was administered through femoral vein injection 30 min before ischemia on the rats in the PMX53 group (n = 18). The saline group (n = 18) was given saline at the same volume through femoral vein injection. The neurologic outcome of the posterior limbs was assessed by the Basso-Beattie-Bresnahan (BBB) score at 1, 6, 12, 24 and 48 h after reperfusion. Histologic changes of the spinal cord were detected with hematoxylin-eosin (H-E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect myeloperoxidase (MPO) activity in the spinal cord. Immunohistochemistry was used to investigate the quantity of activated astrocytes and microglia. Results: After pre-treatment with PMX53, neurologic function improved gradually after 6, 12, 24 and 48 h reperfusion. The BBB score of the PMX53 group increased significantly (Po0.05) compared with the saline group. H-E staining showed that pathologic damage in the PMX53 group was reduced. Moreover, administration of PMX53 significantly inhibited neutrophil infiltration in the spinal cord. Levels of MPO activity in the spinal cord were remarkably lower in the PMX53 group (Po0.05). There were also more activated microglia and astrocytes in the spinal cord of the PMX53 group than in the saline group (Po0.05). INTRODUCTIONSpinal cord ischemia-reperfusion injury (SIRI) mainly occurs after operations on the descending thoracic or thoracoabdominal aorta, such as thoracoabdominal aneurysm. 1 SIRI causes various complications, including paraparesis and paraplegia. 2 These complications have been attributed to temporary or permanent ischemia of the spinal cord caused by interruption of the blood supply during aortic cross-clamping. The incidence of paraplegia has been correlated with dissection, rupture and prolonged clamp times. 3 Systemic hypothermia, spinal fluid drainage and preconditioning ischemia were considered to prevent paraplegia, 4 but the effect was limited. Recent studies indicated that pathophysiological mechanisms underlying SIRI are complicated, including the release of inflammatory factors, 5 calcium overload, 6 oxidative stress, 7 excitotoxicity 8 and neuronal apoptosis. 9,10 In addition, there are more mechanisms that remain unclear. It has been found that the inflammatory cascade is activated due to SIRI, including neutrophil and neuroglia mobilization and infiltration, as well as elevated levels of inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6. 11 The complement system, a major component of the innate immune system, is

C5aR1 Mediates the Progression of Inflammatory Responses in the Brain of Rats in the Early Stage after Ischemia and Reperfusion

“…20−22 The mechanisms of blocking C5aR1 by PMX53 are mostly related to inhibiting inflammation responses including the attenuation of tumor necrosis factor-α (TNF-α) expression in tissue or plasma, inhibiting myeloperoxidase activity, and decreasing the number of neutrophilia and infiltrating neutrophils. 23 These studies suggested that C5aR1 blockade decreased inflammation responses, and blocking C5aR1 signaling pathway may be a favorable modality for the treatment of brain disorders after ischemic stroke. However, in ischemic stroke progression, the pivotal role of C5aR1 contributing to the detrimental outcome in brain tissues remains unclear.…”

“…PMX53 is a specific C5aR1 antagonist with the molecular formula AcF-[OP­(D-Cha)­WR]. The protective role of PMX53 has also been found in I/R injury in multiple organs, including liver, kidney, and limbs. − The mechanisms of blocking C5aR1 by PMX53 are mostly related to inhibiting inflammation responses including the attenuation of tumor necrosis factor-α (TNF-α) expression in tissue or plasma, inhibiting myeloperoxidase activity, and decreasing the number of neutrophilia and infiltrating neutrophils . These studies suggested that C5aR1 blockade decreased inflammation responses, and blocking C5aR1 signaling pathway may be a favorable modality for the treatment of brain disorders after ischemic stroke.…”

The protective effect of betanin and copper on spinal cord ischemia–reperfusion injury

“…Also, the time point (48 h) was chosen as established in this surgical model. 15,32,33 Combination treatment with different carriers and usage of less debilitating models for more time intervals for sampling may be good approaches to extrapolate from our study in the future.…”

Nanofiber Scaffolds as Drug Delivery Systems to Bridge Spinal Cord Injury

“…In the last two years, many research studies, focusing on the identification of drugs potentially effective in SCI treatment, have been published [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ,…”